Impact of an Ultra-Endurance Marathon on Cardiac Function in Association with Cardiovascular Biomarkers.

BACKGROUND: Participation in ultra-endurance races may lead to a transient decline in cardiac function and increased cardiovascular biomarkers. This study aims to assess alterations in biventricular function immediately and five days after the competition in relation to elevation of high-sensitivity cardiac Troponin I (hs-cTnI) and N-terminal-pro-brain-natriuretic-peptide (NT-proBNP). METHODS AND RESULTS: Fifteen participants of an ultramarathon (UM) with a running distance of 130 km were included. Transthoracic echocardiography and quantification of biomarkers was performed before, immediately after and five days after the race. A significant reduction in right ventricular fractional area change (FAC) was observed after the race (48.0 ± 4.6% vs. 46.7 ± 3.8%, p = 0.011) that persisted five days later (48.0 ± 4.6% vs. 46.3 ± 3.9%, p = 0.027). No difference in left ventricular ejection fraction (LVEF) was found (p = 0.510). Upon stratification according to biomarkers, participants with NT-proBNP above the median had a significantly reduced LVEF directly (60.8 ± 3.6% vs. 56.9 ± 4.8%, p = 0.030) and five days after the race (60.8 ± 3.6% vs. 55.3 ± 4.5%, p = 0.007) compared to baseline values. FAC was significantly reduced five days after the race (48.4 ± 5.1 vs. 44.3 ± 3.9, p = 0.044). Athletes with hs-cTnI above the median had a significantly reduced FAC directly after the race (48.1 ± 4.6 vs. 46.5 ± 4.4, p = 0.038), while no difference in LVEF was observed. No alteration in cardiac function was observed if hs-cTnI or NT-proBNP was below the median. CONCLUSION: A slight decline in cardiac function after prolonged strenuous exercise was observed in athletes with an elevation of hs-cTnI and NT-proBNP above the median but not below.

Omission of Antiplatelet Therapy in Patients With HeartMate 3 Left Ventricular Assist Devices: A Systematic Review and Meta-Analysis.

The HeartMate 3 (HM3) left ventricular assist device has decreased thromboembolic events and minimized the risk of pump thrombosis. However, bleeding complications due to combined antithrombotic therapy with a vitamin K antagonist (VKA) and aspirin remain high. Only limited data on the safety of VKA monotherapy in HM3 patients are available. A systematic search on the main databases was performed. Observational data and randomized trials were eligible for this analysis. As primary endpoint, we analyzed hemocompatibility-related adverse events (HRAE). As secondary endpoints, we investigated the individual components of the primary endpoint. The analysis was carried out using the odds ratio (OR) as outcome measure. A random-effects model was fitted to the data. Five manuscripts fulfilled the inclusion criteria. These trials included 785 patients (381 on VKA monotherapy, 404 on VKA and aspirin). VKA monotherapy significantly reduced HRAE (OR: 0.11 [95% confidence interval {CI}: 0.02-0.59], p = 0.01, I2 = 87%). The reduction was driven by a decrease in bleeding complications (OR: 0.12 [95% CI: 0.02-0.62], p = 0.01, I2 = 86%) without increasing the rates of thromboembolic events (OR: 0.69 [95% CI: 0.26-1.81], p = 0.45, I = 0%). Vitamin K antagonist monotherapy is associated with a significant reduction of bleeding events without increasing the risk of thromboembolic complications in HM3 patients.

Anticoagulation in atrial fibrillation and end-stage kidney disease on hemodialysis: a meta-analysis of randomized trials comparing direct oral anticoagulants with vitamin K antagonists.

Background: Only small randomized trials have investigated the efficacy and safety of direct oral anticoagulants (DOACs) compared with vitamin K antagonists (VKAs) in patients with non-valvular atrial fibrillation (NVAF) and end-stage kidney disease. Objectives: To perform a systematic review and meta-analysis comparing anticoagulation with DOACs to VKAs in patients with NVAF undergoing chronic hemodialysis. Methods: A systematic search using Medline, Web of Science, and Embase was performed. All randomized trials comparing DOACs with VKAs in patients with NVAF undergoing chronic hemodialysis were included. As primary endpoint, we analyzed all-cause mortality. As secondary endpoints, we investigated total bleeding events, life-threatening or major bleeding events, and thromboembolic events or stroke. We used the odds ratio as outcome measure and fitted a random-effects model due to the expected heterogeneity. Results: Three studies fulfilled the inclusion criteria comprising 383 patients (218 on apixaban or rivaroxaban, 165 on VKA). No significant difference between DOACs and VKAs regarding death (OR, 0.94; 95% CI, 0.55-1.63; p = .84), total bleedings (OR, 0.99; 95% CI, 0.63-1.54; p = .96) and life-threatening or major bleeding (OR, 0.65; 95% CI, 0.32-1.33, p = .24) was detected. There was a trend toward a reduction of thromboembolic events or stroke in patients receiving DOACs (OR, 0.39; 95% CI, 0.14-1.05; p = .06). Conclusion: Orally administered activated factor X inhibitors carried a similar risk of bleeding and death when compared with VKAs in patients with NVAF undergoing chronic hemodialysis. Moreover, there was a trend towards a reduction of thromboembolic events or stroke in patients receiving DOACs.

The LIPL study: Postprandial lipid profile, inflammation, and platelet activity in patients with chronic coronary syndrome.

Background and aims: It is suggested that the changes in atherosclerosis happen mainly under the influence of non-fasting lipids. To date, the studies in the postprandial state were primarily performed on healthy subjects. This exploratory, cross-sectional study investigates the change in lipid profile, inflammation, and platelet activation in patients with different cardiovascular risk profiles in the postprandial state. Methods: The studied population consists of 66 patients with different cardiovascular risks: patients with a history of the chronic coronary syndrome (CCS) and diabetes mellitus type 2 (DM2) (n = 20), CCS without DM2 (n = 25), and a healthy control group (n = 21). Lipid variables and markers of platelet function and inflammation were assessed during the fasting state and three and 5 h after a standardized fat meal using a standardized oral fat tolerance test (OFTT), a milkshake with 90 g of fat. Results: Patients with CCS and DM2 were significantly older and had the highest BMI. All patients with CCS were on acetylsalicylic acid, and 95% of CCS patients were on high-dose statins. The absolute leukocyte and neutrophile count increased significantly in the control group during the OFTT in comparison to CCS subjects. There was a significant decrease of HDL and increase of triglycerides during the OFTT, however with no difference between groups. There was no difference in the change of platelet activity between all groups. Conclusion: This study showed that OFTT leads to an increased postprandial inflammation response in healthy group compared to CCS ± DM2 while there was no change in lipid profile and platelet activity.

Cardiovascular events in patients treated with bempedoic acid vs. placebo: systematic review and meta-analysis.

AIMS: Reduction of low-density lipoprotein cholesterol (LDL-C) decreases cardiovascular mortality and morbidity. Bempedoic acid represents a promising novel lipid-modifying agent for patients who cannot reach guideline recommended LDL-C goals or statin-intolerant patients, but data on safety and cardiovascular outcomes are limited. We therefore aimed to systematically review randomized controlled trials investigating bempedoic acid vs. placebo in patients with hyperlipidaemia. METHODS: A systematic search on the databases PubMed, Web of Science, and Embase until 20 March 2023 was performed. All randomized trials comparing bempedoic acid (180 mg daily) with placebo in patients with an indication for lipid-lowering therapy were included. As a primary endpoint, we analysed three-point major adverse cardiovascular events (MACEs) consisting of cardiovascular death, non-fatal myocardial infarction (MI), or non-fatal stroke. The analysis was carried out using the odds ratio (OR) as the outcome measure. Due to the expected heterogeneity across studies, a random-effects model was fitted to the data. RESULTS: Out of 258 manuscripts, 10 manuscripts fulfilled the inclusion criteria. In total, these trials included 18 200 patients (9765 on bempedoic acid, 8435 on placebo). Bempedoic acid significantly reduced MACEs compared with placebo (OR 0.84 [95% confidence interval (CI) 0.76-0.96]; P < 0.001; I2 = 0%). The endpoint reduction was driven by a lower rate of non-fatal MI, whereas bempedoic acid had no significant effect on stroke (OR 0.86 [95% CI 0.69-1.08]; P = 0.20, I2 = 0%) and all-cause mortality (OR 1.19 [95% CI 0.73-1.93]; P = 0.49; I2 = 18%). CONCLUSION: Bempedoic acid reduced non-fatal MI in patients with hyperlipidaemia, whereas it had no significant effect on stroke and all-cause mortality.

Growth Differentiation Factor 15 Is Associated with Platelet Reactivity in Patients with Acute Coronary Syndrome.

Bleeding events in patients with acute coronary syndrome (ACS) are a risk factor for adverse outcomes, including mortality. We investigated the association of growth differentiation factor (GDF)-15, an established predictor of bleeding complications, with on-treatment platelet reactivity in ACS patients undergoing coronary stenting receiving prasugrel or ticagrelor. Platelet aggregation was measured by multiple electrode aggregometry (MEA) in response to adenosine diphosphate (ADP), arachidonic acid (AA), thrombin receptor-activating peptide (TRAP, a protease-activated receptor-1 (PAR-1) agonist), AYPGKF (a PAR-4 agonist) and collagen (COL). GDF-15 levels were measured using a commercially available assay. GDF-15 correlated inversely with MEA ADP (r = -0.202, p = 0.004), MEA AA (r = -0.139, p = 0.048) and MEA TRAP (r = -0.190, p = 0.007). After adjustment, GDF-15 was significantly associated with MEA TRAP (ß = -0.150, p = 0.044), whereas no significant associations were detectable for the other agonists. Patients with low platelet reactivity in response to ADP had significantly higher GDF-15 levels (p = 0.005). In conclusion, GDF-15 is inversely associated with TRAP-inducible platelet aggregation in ACS patients treated with state-of-the-art antiplatelet therapy and significantly elevated in patients with low platelet reactivity in response to ADP.

Antiplatelet Therapy in Coronary Artery Disease: Now and Then.

Cardiovascular disease, particularly coronary artery disease (CAD), remains the leading cause of mortality and morbidity in industrialized countries. Platelet activation and aggregation at the site of endothelial injury play a key role in the processes ultimately resulting in thrombus formation with vessel occlusion and subsequent end-organ damage. Consequently, antiplatelet therapy has become a mainstay in the pharmacological treatment of CAD. Several drug classes have been developed over the last decades and a broad armamentarium of antiplatelet agents is currently available. This review portrays the evolution of antiplatelet therapy, and provides an overview on previous and current antiplatelet drugs and strategies.

Impact of ABO Blood Group on Thromboembolic and Bleeding Complications in Patients with Left Ventricular Assist Devices.

BACKGROUND: The ABO blood group system is linked to hemostasis via its relationship with von Willebrand factor (VWF) and factor VIII (FVIII). In the current study, we investigated the association of the ABO system with clinical outcomes as well as VWF and platelet function in patients with left ventricular assist devices (LVADs). METHODS: Bleeding and thromboembolic complications were assessed in 111 patients during 1 year after LVAD implantation. In 67 LVAD patients, VWF antigen, VWF activity, VWF ristocetin cofactor, VWF collagen-binding, and FVIII activity were assessed. Platelet surface P-selectin and activated glycoprotein IIb/IIIa were determined by flow cytometry, and soluble P-selectin was measured with an enzyme-linked immunoassay. Platelet aggregation was assessed by light transmission and impedance aggregometry. RESULTS: Thirty-six patients (32.4%) experienced a bleeding and 22 patients (19.8%) a thromboembolic event. In univariate analyses, patients with blood group O had numerically more bleeding complications and less thromboembolic events as compared to patients with blood group non-O (both p ≥ 0.05). After multivariable adjustment, blood group O was significantly associated with a higher risk of bleeding (hazard ratio 2.42 [95% confidence interval 1.03-5.70], p = 0.044) but not linked to thromboembolic complications. CONCLUSION: Patients with blood group O had significantly lower levels of VWF and FVIII (all p < 0.05), whereas P-selectin expression in response to thrombin-receptor activating peptide and soluble P-selectin were higher as compared to patients with blood group non-O (both p < 0.05). LVAD patients with blood group O are at an increased bleeding risk, potentially due to lower VWF and FVIII levels.

Pharmacist interventions to improve blood pressure control in primary care: a cluster randomised trial.

BACKGROUND: High blood pressure (BP) is the single largest contributor to mortality world-wide. AIM: To investigate the effectiveness of a pharmacists-led intervention to improve BP control using automated office blood pressure (AOBP). METHOD: In this prospective parallel group, unblinded, cluster-randomised trial, 54 pharmacies enrolled pre-treated patients with uncontrolled AOBP above 135/85 mmHg. In the interventional group, pharmacists referred patients to the treating physician for therapy intensification in a structured fashion. In the control group, AOBP was recorded until the end of the trial. The primary endpoint was the proportion of patients achieving BP control at the threshold of 135/85 mmHg after 10 weeks. Key secondary endpoints were systolic AOBP reductions after 10 and 20 weeks. RESULTS: A total of 497 patients were included between 2017 and 2019. In the interventional and control group, 61.5% and 19.8% of patients underwent a therapy modification within 20 weeks. The primary endpoint was achieved in 38.8% in the interventional group and 31.2% in the control group (mean difference 7.6%, 95% CI -8.1; 23.3, p = 0.336). Mean systolic AOBP reductions were greater in the interventional vs. control group at 10 and 20 weeks (14.3 ± 7.4 vs. 6.9 ± 7.0 mmHg, mean difference 7.3 mmHg, 95% CI 3.2;11.5, p < 0.001, and 15.5 ± 9.0 vs. 9.8 ± 7.5 mmHg, mean difference 5.8 mmHg, 95% CI 0.8;10.7, p = 0.023). Atrial fibrillation was newly detected in 7.8% of patients. CONCLUSION: Through a pragmatic pharmacist-led disease management program, BP control was improved over time, without significant differences between groups. Greater systolic AOBP reductions were observed in the interventional vs. control group. (Pharmacists Intervention to Improve Hypertension Management in Primary Care:APOTHECARE; ClinicalTrials.gov registration NCT03274531).

Growth Differentiation Factor-15 Correlates Inversely with Protease-Activated Receptor-1-Mediated Platelet Reactivity in Patients with Left Ventricular Assist Devices.

Growth differentiation factor (GDF)-15 inhibits platelet activation, prevents thrombus formation, and has been linked to bleeding events. This was a prospective study including 51 left-ventricular assist device (LVAD) patients on aspirin and phenprocoumon. Platelet surface expression of activated glycoprotein (GP) IIb/IIIa was assessed by flow cytometry, and platelet aggregation was measured by multiple electrode aggregometry (MEA) in response to arachidonic acid (AA), adenosine diphosphate (ADP), and thrombin receptor-activating peptide (TRAP), a protease-activated-receptor-1 (PAR-1) agonist. GDF-15 was determined with a commercially-available assay. There was a trend towards an inverse correlation of GDF-15 with activated GPIIb/IIIa in response to TRAP (r = -0.275, p = 0.0532) but not in response to AA and ADP. Moreover, GDF-15 correlated with MEA TRAP (r = -0.326, p = 0.0194), whereas it did not correlate with MEA ADP and MEA AA. In a second step, GDF-15 levels in the fourth quartile were defined as high GDF-15. Patients with high GDF-15 showed significantly lower TRAP-inducible platelet aggregation by MEA compared to patients in the first quartile (63 AU vs. 113 AU, p = 0.0065). In conclusion, in LVAD patients receiving state-of-the-art antithrombotic therapy, GDF-15 correlates inversely with residual platelet reactivity via PAR-1.

Platelet-to-Lymphocyte Ratio as Marker of Platelet Activation in Patients on Potent P2Y12 Inhibitors.

A high platelet-to-lymphocyte ratio (PLR) has recently been associated with ischemic outcomes in cardiovascular disease. Increased platelet reactivity and leukocyte-platelet aggregate formation are directly involved in the progress of atherosclerosis and have been linked to ischemic events following percutaneous coronary intervention (PCI). In order to understand the relation of PLR with platelet reactivity, we assessed PLR as well as agonist-inducible platelet aggregation and neutrophil-platelet aggregate (NPA) formation in 182 acute coronary syndrome (ACS) patients on dual antiplatelet therapy with aspirin and prasugrel (n = 96) or ticagrelor (n = 86) 3 days after PCI. PLR was calculated from the blood count. Platelet aggregation was measured by multiple electrode aggregometry and NPA formation was determined by flow cytometry, both in response to ADP and SFLLRN. A PLR ≥91 was considered as high PLR based on previous data showing an association of this threshold with adverse ischemic outcomes. In the overall cohort and in prasugrel-treated patients, high PLR was associated with higher SFLLRN-inducible platelet aggregation (67 AU [50-85 AU] vs 59.5 AU [44.3-71.3 AU], P = .01, and 73 AU [50-85 AU] vs 61.5 AU [46-69 AU], P = .02, respectively). Further, prasugrel-treated patients with high PLR exhibited higher ADP- (15% [11%-23%] vs 10.9% [7.6%-15.9%], P = .007) and SFLLRN-inducible NPA formation (64.3% [55.4%-73.8%] vs 53.8% [44.1%-70.1%], P = .01) as compared to patients with low PLR. These differences were not seen in ticagrelor-treated patients. In conclusion, high PLR is associated with increased on-treatment platelet reactivity in prasugrel-treated patients, but not in patients on ticagrelor.

Neurotensin and Adverse Cardiovascular Outcomes in Patients Undergoing Percutaneous Coronary Intervention.

Background: Neurotensin is involved in fatty acid and glucose metabolism and promotes the development of obesity and diabetes. These associations appear to be more pronounced in women. We investigated the association of neurotensin with long-term major adverse cardiovascular events (MACE) in patients presenting with acute coronary syndrome (ACS) or chronic coronary syndrome (CCS) undergoing percutaneous coronary intervention (PCI). Methods: We included 452 consecutive patients [144 (31.9%) females] undergoing PCI for ACS or CCS. Plasma samples drawn after PCI were analyzed for neurotensin with an enzyme-linked immunoassay. As primary endpoint, a composite of MACE including all-cause death, non-fatal myocardial infarction and non-fatal stroke during 7 years of follow-up was investigated. As secondary endpoint, we investigated all-cause death. Results: Neurotensin levels did not differ between male and female patients (p = 0.560). MACE occurred in 150 (33.2%) patients. Restricted cubic splines demonstrated a U-shaped association of log-transformed neurotensin with the primary and secondary endpoint. Therefore, we dichotomized our cohort according to tertiles of log-transformed neurotensin. In Kaplan-Meier analysis including the total cohort and restricted to male patients log- neurotensin tertiles were not associated with MACE (both p > 0.05). Moreover, in the overall cohort and in male patients multivariable Cox regression analysis log-neurotensin tertiles were not associated with MACE or with all-cause death (all p > 0.05). However, in female patients log-neurotensin was associated with MACE in Kaplan-Meier analysis (log-rank p = 0.013). Also, after multivariable adjustment female patients in the first tertile had a significantly increased risk for MACE compared to female patients in the second tertile [HR 3.84 (95% CI 1.71-8.60), p = 0.001]. There was tendency for increased risk in female patients in the third tertile compared to the second tertile [HR 2.14 (95% CI 0.97-4.73), p = 0.058]. Moreover, in female patients the [first and the third tertile of log- neurotensin were associated with all-cause death 1s vs. 2nd tertile: HR 3.03 (95% CI 1.21-7.63), p = 0.018; 3rd vs. 2nd tertile: HR 3.01 (95% CI 1.22-7.44), p = 0.016]. Conclusion: In female patients with CAD undergoing PCI, neurotensin has a U-shaped relationship with adverse outcomes. These data suggest a sex specific association between neurotensin and long-term adverse events after PCI.

Platelet activation and aggregation in different centrifugal-flow left ventricular assist devices.

Left-ventricular assist devices (LVADs) improve outcomes in end-stage heart failure patients. Two centrifugal-flow LVAD systems are currently approved, HeartMate 3 (HM3) and Medtronic/Heartware HVAD (HVAD). Clinical findings suggest differences in thrombogenicity between both systems. We compared markers of platelet activation and aggregation between HM3 and HVAD. We prospectively included 59 LVAD patients (40 HM3, 19 HVAD). Platelet P-selectin expression, activated glycoprotein (GP) IIb/IIIa and monocyte-platelet aggregates (MPA) were assessed by flow-cytometry. Platelet aggregation was measured by light-transmission aggregometry (LTA) and multiple-electrode aggregometry (MEA). Von-Willebrand factor (VWF) antigen (VWF:Ag), VWF activity (VWF:Ac), and VWF multimer pattern analysis were determined. Soluble P-selectin (sP-selectin) was measured with an enzyme-linked immunoassay. P-selectin, GPIIb/IIIa and MPA levels in vivo and in response to arachidonic acid, adenosine diphosphate, and thrombin receptor activating peptide were similar between HM3 and HVAD (all p > .05). Likewise, agonist-inducible platelet aggregation by LTA and MEA did not differ between HM3 and HVAD (all p > .05). VWF:Ag levels and FVIII:C were similar between both systems (both p > .05), but patients with HVAD had significantly lower VWF:Ac (p = .011) and reduced large VWF multimers (p = .013). Finally, sP-selectin levels were similar in patients with HVAD and HM3 (p = .845). In conclusion, on-treatment platelet activation and aggregation are similar in HM3 and HVAD patients. Potential clinical implications of observed differences in VWF profiles between both LVAD systems need to be addressed in future clinical trials.

Sex-specific platelet activation through protease-activated receptor-1 in patients undergoing cardiac catheterization.

BACKGROUND AND AIMS: Protease-activated receptor (PAR)-1-mediated platelet activation may vary according to sex and clinical situation. In order to investigate sex-specific platelet activation through PAR-1, we assessed platelet response to thrombin receptor-activating peptide (TRAP) in 562 patients undergoing cardiac catheterization without (Group 1A) and with (Group 1B) acute coronary syndrome (ACS). Subsequently, we sought to confirm our findings in 287 patients undergoing elective (Group 2A) or acute (Group 2B) percutaneous coronary intervention. METHODS: TRAP-stimulated platelet surface expression of P-selectin and activated glycoprotein IIb/IIIa (GPIIb/IIIa) were measured by flow cytometry in Group 1. Light transmission aggregometry (LTA) and multiple electrode aggregometry (MEA) in response to TRAP were assessed in Group 2. RESULTS: In Group 1A, platelet activation in response to TRAP was significantly higher in women compared to men (P-selectin: 511 MFI [443-597 MFI] vs. 471 MFI [393-552 MFI]; GPIIb/IIIa: 84 MFI [58-119 MFI] vs. 70 MFI [47-103 MFI]; both p ≤ 0.002). In contrast, in Group 1B, TRAP-stimulated P-selectin and activated GPIIb/IIIa were similar in men and women (both p ≥ 0.3). Likewise, TRAP-stimulated platelet aggregation was significantly higher in female patients in Group 2A (LTA: 66% [54-76%] vs. 51% [41-65%]; MEA: 78 AU [66-107 AU] vs. 62 AU [52-88 AU]; both p ≤ 0.02), whereas men and women in Group 2 B had similar platelet aggregation (p = 0.5). The occurrence of ischemic endpoints did not differ significantly between men and women in Group 1A and Group 1B. CONCLUSIONS: Platelet PAR-1 signaling is more pronounced in women than in men without ACS. In ACS, however, PAR-1-mediated platelet activation is similar in male and female patients.

Upstream Statin Therapy and Long-Term Recurrence of Atrial Fibrillation after Cardioversion: A Propensity-Matched Analysis.

The relationship of statin therapy with recurrence of atrial fibrillation (AF) after cardioversion (CV) has been evaluated by several investigations, which provided conflicting results and particularly long-term data is scarce. We sought to examine whether upstream statin therapy is associated with long-term recurrence of AF after CV. This was a single-center registry study including consecutive AF patients (n = 454) undergoing CV. Cox regression models were performed to estimate AF recurrence comparing patients with and without statins. In addition, we performed a propensity score matched analysis with a 1:1 ratio. Statins were prescribed to 183 (40.3%) patients. After a median follow-up period of 373 (207-805) days, recurrence of AF was present in 150 (33.0%) patients. Patients receiving statins had a significantly lower rate of AF recurrence (log-rank p < 0.001). In univariate analysis, statin therapy was associated with a significantly reduced rate of AF recurrence (HR 0.333 (95% CI 0.225-0.493), p = 0.001), which remained significant after adjustment (HR 0.238 (95% CI 0.151-0.375), p < 0.001). After propensity score matching treatment with statins resulted in an absolute risk reduction of 27.5% for recurrent AF (21 (18.1%) vs. 53 (45.7%); p < 0.001). Statin therapy was associated with a reduced risk of long-term AF recurrence after successful cardioversion.

Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers in Acute Coronary Syndrome: Implications for Platelet Reactivity?

BACKGROUND: In patients with acute coronary syndrome (ACS), angiotensin-converting enzyme (ACE) inhibitors are preferred over angiotensin receptor blockers (ARBs). However, in a recent pilot study, treatment with ACE inhibitors was associated with increased platelet reactivity compared to ARBs. Therefore, we sought to investigate the impact of renin-angiotensin-aldosterone system (RAAS) blockade with ACE inhibitors and ARBs on platelet aggregation in patients with ACS undergoing percutaneous coronary intervention. METHODS: On-treatment residual platelet reactivity in response to arachidonic acid (AA), adenosine diphosphate (ADP), SFLLRN, AYPGKF, and collagen was assessed by multiple electrode aggregometry (MEA) in 197 ACS patients on dual antiplatelet therapy (DAPT) with aspirin and either prasugrel or ticagrelor. RESULTS: One hundred sixty-five (83.7%) patients were treated with ACE inhibitors, 32 (16.3%) with ARBs. On-treatment residual AA- and ADP-inducible platelet reactivity was significantly higher in patients with ACE inhibitors (both p < 0.05). Likewise, SFLLRN was significantly higher in patients with ACE inhibitors (p = 0.036) and there was a trend for higher AYPGKF- and collagen-inducible platelet reactivity (p = 0.053 and p = 0.082). The incidence of high on-treatment residual platelet reactivity AA was significantly higher in patients with ACE inhibitors (52 [31.5%] vs. 3 [9.4%] patients; p = 0.019). CONCLUSION: ACE inhibitors are associated with increased on-treatment residual platelet reactivity in ACS patients with potent DAPT. Further clinical trials are needed to elucidate the role of RAAS blockade with ACE inhibitors and ARBs in ACS patients treated according to current standards.

Mean Corpuscular Volume Predicts Adverse Outcomes Following Peripheral Angioplasty With Stenting and Is Associated With On-Treatment Platelet Reactivity.

Structural aspects of red blood cells have been associated with cardiovascular disease. No data linking mean corpuscular volume (MCV) to clinical outcomes and on-treatment platelet reactivity in patients with peripheral artery disease (PAD) are available. We investigated a composite of atherothrombotic events and target vessel restenosis or reocclusion following infrainguinal stenting for stable PAD. Residual platelet reactivity was measured by light transmission aggregometry (LTA) and the VerifyNow assays. We included 104 patients receiving dual antiplatelet therapy (DAPT) with aspirin and clopidogrel. In receiver-operating characteristic analysis, MCV effectively discriminated between patients with and without adverse outcomes and identified a MCV ≤90.8 fL as optimal cutoff. Adverse outcomes occurred significantly more often in patients with low MCV (log-rank P = .002). In univariable Cox regression analysis, low MCV was associated with an increased risk of future adverse outcomes (hazard ratio [HR]: 2.662 [95%CI: 1.304-5.434]; P = .007) and remained significantly associated after adjustment (HR: 2.591 [95%CI: 1.242-5.403]; P = .011). Mean corpuscular volume was inversely correlated with arachidonic acid (AA)- and adenosine diphosphate (ADP)-inducible platelet reactivity by LTA and with the VerifyNow aspirin assay. Low MCV is associated with adverse outcomes over 2 years following infrainguinal stenting. Mean corpuscular volume correlates inversely with AA- and ADP-inducible platelet reactivity during DAPT.

Effect of marathon and ultra-marathon on inflammation and iron homeostasis.

The physiological response to high-level endurance exercise, such as running a marathon, poses several beneficial but also potentially harmful metabolic changes. The objective of this study was to determine the impact of marathon (M) and ultra-marathon (UM) on inflammation and iron homeostasis in paired samples. Fifteen well-trained, non-professional endurance athletes (14 males, 1 female) performed both a 130 km ultra-marathon and a traditional 42.195 km marathon. We determined markers of inflammation and iron homeostasis before, immediately after, and within 5 days after finishing each run, respectively. Biomarkers of inflammation (leucocytes, neutrophil granulocytes, monocytes, and c-reactive protein [CRP]) increased significantly after both marathon and ultra-marathon with higher levels of CRP after ultra-marathon compared with marathon both immediately after the race (18.15 ± 12.41 vs 5.58 ± 9.65 mg/L, P < .001) and at follow-up (15.67 ± 16.97 vs 7.19 ± 7.75 mg/L, P = .045) Concentrations of ferritin also increased significantly after both races and remained high at follow-up. Higher levels of ferritin immediately after the race (111.5 ± 103.2 vs 84.8 ± 86.3, P = .001) and at follow-up (102.7 ± 79.5 vs 74.6 ± 65.6, P = .001) were found in ultra-marathon finishers. The observed increase of serum iron and transferrin saturation (TSAT) after marathon and the decrease of serum iron and TSAT after ultra-marathon resulted in a significant absolute difference between the two races. The present data suggest a higher degree of inflammation after ultra-marathon compared with marathon. Markers of iron homeostasis also showed different response patterns with regard to running distance.

Von Willebrand Factor and ADAMTS13 and long-term outcomes in patients undergoing percutaneous coronary intervention.

BACKGROUND: Von Willebrand factor (VWF) and its cleaving protease a disintegrin-like and metalloprotease with thrombospondin type I repeats 13 (ADAMTS13) are pivotal mediators of thrombosis and are associated with the progression of atherosclerosis. We investigated the impact of VWF, ADAMTS13 and VWF/ADAMTS13 on long-term major adverse cardiovascular outcomes (MACE) in patients undergoing percutaneous coronary intervention (PCI). METHODS: We analysed 701 patients undergoing PCI between 2003 and 2006. VWF and ADAMTS13 antigen levels were measured before PCI. As primary endpoint, we investigated MACE, a composite of all-cause mortality, myocardial infarction or ischemic stroke during 8 years of follow-up. As secondary endpoint, we investigated all-cause mortality. RESULTS: Mean age was 63.8 years, 496 (70.8%) were male. Acute coronary syndrome (ACS) was diagnosed in 347 (49.5%) patients, stable coronary artery disease (SCAD) in 354 (50.5%). During follow-up 228 (32.5%) patients experienced MACE, and 161 (23.0%) died. In ACS patients, VWF was significantly associated with MACE (HR 1.402 (95%CI 1.003-1.959), p = 0.048), whereas ADAMTS13 and VWF/ADAMTS13 had no predictive value. In SCAD, neither VWF, ADAMTS13, nor VWF/ADAMTS13 correlated with MACE. VWF was significantly associated with all-cause death in ACS patients (HR 1.841 (95%CI 1.187-2.856), p = 0.006), but not in SCAD (1.394 (95%CI 0.856-2.269), p = 0.181). ADAMTS13 and VWF/ADAMTS13 were not correlated with ACS and SCAD, respectively. CONCLUSION: VWF but not ADAMTS13 and VWF/ADAMTS13 was associated with MACE and mortality in patients with ACS but not SCAD. This finding highlights the importance of VWF as an essential marker of risk in patients with ACS.